The need for new classes of chemical compounds for use in pharmaceutical and agricultural applications has received much attention. For example, modem synthetic chemical methods for producing regio- and stereochemically defined compounds have made possible drugs with previously unattainable activity and specificity. Nevertheless, many currently-available drugs have been designed to avoid structural complexity, due to the traditionally difficult task of economically developing compounds with dense and diverse functional arrays. Thus, new methods for the production of functionally and stereochemically diverse compounds have the potential to exploit this heretofore underexplored area.
Transition-metal mediated olefin metathesis has been recognized as an effective means for carbon-carbon bond formation (see, e.g., Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. (1995) 28:446; Schmalz, H. -G. Angew. Chem. Int. Ed Engl. (1995) 34(17):1833). Ring closing-metathesis has been extensively utilized for the synthesis of macrocycles, carbocycles and heterocycles (see (a) Fu, G. C. Grubbs, R. H. J. Am. Chem. Soc. (1992) 114:5426. (b) Fu, G. C. Grubbs, R. H. J Am. Chem. Soc. (1992) 114:7324. (c) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:3800. (d) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:9856. (e) Fujimura, O.; Fu. G. C.; Grubbs, R. H. J. Org. Chem. (1994) 59:4029. (f) Kim, S. -H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. (1994) 116:10801. (g) Miller, S. J.; Kim, S. -H.; Chen, Z. -R; Grubbs, R. H. J. Am. Chem Soc. (1995) 117:2108. (h) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. (1995) 117:5855. (i) Martin, S. F.; Liao, Y.; Rein, T. Tetrahedron Lett. (1994) 35:691. (j) Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. (1994) 35:3191. (k) Martin, S. F.; Liao, Y.; Chen. H. J.; Patzel, M.; Ramser, M. N. Tetrahedron Lett. (1994) 35:6005. (1) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. (1995) 36:1169. (m) Houri, A. F.; Xu, Z.; Cogan, D.; Hoveyda, A. J. Am. Chem. Soc. (1995) 117:2943. (n) Kim, S. -H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. (1996) 61:1073. (o) Furstner, A.; Langemann, K . J. Org. Chem. (1996) 61:3942. (p) Crimmins, M. T.; King, B. W. J. Org. Chem. (1996) 61:4192. (q) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. (1996) 118:6634). However, the application of intermolecular ring opening cross-metathesis (ROM) for the convergent synthesis of small organic molecules has remained relatively unexplored. Recently, solution-phase ROM of fused and bicyclic olefin systems with aliphatic alkenes yielding cyclopentane and tetrahydrofuran derivatives was reported (see (a) Schneider, M. F.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1996) 35: 411. (b) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc. (1995) 117:9610. (c) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1997) 36: 257). (d) Snapper et al. J. Am. Chem. Soc. 119:1478 (1997)). For unsymmetrically substituted substrates only slight regioselectivity was generally observed. In addition, other reaction pathways, such as ring opening metathesis polymerization of the bicyclic or fused olefins competed with the desired cross-metathesis reactions.
Terminal aryl olefins have been shown to participate in selective cross-metathesis reactions utilizing a molybdenum alkylidene catalyst (see Crowe, W. E.; Zhang, Z. J. J. Am. Chem. Soc. (1993) 115:10998). The cross-metathesis of norbornene and styrene in the presence of Ru.sub.2 (OAc).sub.4 and ethyldiazoacetate has also been reported (see Noels, A. F.; Demonceau, A.; Carlier, E.; Hubert A. J.; Marquez-Silva, R. -L.; Sanchez-Delgado, R. A. J. Chem. Soc., Chem. Commun. (1988) 783). However, an extensive utilization of aryl olefins in ROM has been absent.
Thus, previously reported ROM methods suffer from drawbacks which can render them undesirable for the synthesis of highly complex chemical compounds.